The invention relates to methods of micronizing hydrophobic drugs and related products and methods of using the micronized hydrophobic drugs.
Many hydrophobic agents, both active and non-active have utility in a variety of in vivo settings. Although techniques exist for preparing and formulating hydrophobic agents, these techniques are limited. Some methods of formulation cause a loss of bioactivity. Other methods produce large drug particles or particles of inconsistent sizes that lead to problems in drug delivery.
One method for formulating hydrophobic agents involves the generation of microparticles. Microparticles, microcapsules and microspheres (hereinafter xe2x80x9cmicroparticlesxe2x80x9d) have important applications in the pharmaceutical, agricultural, textile and cosmetics industry as delivery vehicles. In these fields of application, a drug, protein, hormone, peptide, fertilizer, pesticide, herbicide, dye, fragrance or other agent is encapsulated in a polymer matrix and delivered to a site either instantaneously or in a controlled manner in response to some external impetus (i.e., pH, heat, water, radiation, pressure, concentration gradients, etc.). Microparticle size can be an important factor in determining the release rate of the encapsulated material.
Many microencapsulation techniques exist which can produce a variety of particle types and sizes under various conditions. Methods typically involve solidifying emulsified liquid polymer droplets by changing temperature, evaporating solvent, or adding chemical cross-linking agents. Physical and chemical properties of the encapsulant and the material to be encapsulated can sometimes dictate the suitable methods of encapsulation, making only certain methodologies useful in certain circumstances. Factors such as hydrophobicity, molecular weight, chemical stability, and thermal stability affect encapsulation. Significant losses are frequently associated with multiple processing steps. These parameters can be particularly important in respect of encapsulating bioactive agents because losses in the bioactivity of the material due to the processing steps or low yields can be extremely undesirable.
In some aspects, the invention involves a method of micronizing hydrophobic drugs. The micronized drugs prepared by these methods have a variety of properties that are advantageous in the field of drug delivery. For instance, the methods of the invention allow for the formation of particles that have an average particle size of less than 1 micron. The micronized drugs also exhibit enhanced crystallinity and may be used to prepare particles which result in improved relative bioavailability when administered to a subject. Several of these surprising properties are demonstrated in the examples section below.
According to one aspect of the invention, a method for micronizing a hydrophobic agent is provided. A hydrophobic agent is dissolved in an effective amount of a first solvent that is free of polymer. The hydrophobic agent and the solvent form a mixture having a continuous phase. A second solvent and then an aqueous solution arc introduced into the mixture. The introduction of the aqueous solution causes precipitation of the hydrophobic agent and produces a composition of micronized hydrophobic agent having an average particle size of 1 micron or less.
According to another aspect of the invention, a method for micronizing a hydrophobic agent is provided. A hydrophobic agent is dissolved in an effective amount of a first solvent with a polymer. The hydrophobic agent and the first solvent form a mixture having a continuous phase. A second solvent and then an aqueous solution is introduced into the mixture. The introduction of the aqueous solution causes precipitation of the hydrophobic agent to produce a composition of micronized hydrophobic agent having an average particle size of 1 micron or less. In one embodiment, the final preparation contains less than 5% polymer. In yet another embodiment, the polymer is removed by the aqueous solution.
The hydrophobic agent may be dissolved in the first solvent in a variety of ways depending on the agent. Such methods include, but are not limited to, heating, sonicating, high shearing, or high stirring the hydrophobic agent in the first solvent.
The second solvent is optionally an alcohol selected from the group consisting of: methanol (methyl alcohol), ethanol, (ethyl alcohol), 1-propanol (n-propyl alcohol), 2-propanol (isopropyl alcohol), 1-butanol (n-butyl alcohol), 2-butanol (sec-butyl alcohol), 2-methyl-1-propanol (isobutyl alcohol), 2-methyl-2-propanol (t-butyl alcohol), 1-pentanol (n-pentyl alcohol), 3-methyl-1-butanol (isopentyl alcohol), 2,2-dimethyl-1-propanol (neopentyl alcohol), cyclopentanol (cyclopentyl alcohol), 1-hexanol (n-hexanol), cyclohexanol (cyclohexyl alcohol), 1-heptanol (n-heptyl alcohol), 1-octanol (n-octyl alcohol), 1-nonanol (n-nonyl alcohol), 1-decanol (n-decyl alcohol), 2-propen-1-ol (allyl alcohol), phenylmethanol (benzyl alcohol), diphenylmethanol (diphenylcarbinol), triphenylmethanol (triphenylcarbinol), glycerin, phenol, 2-methoxyethanol, 2-ethoxyethanol, 3-ethoxy-1,2-propanediol, Di(ethylene glycol) methyl ether, 1,2-propanediol, 1,3-propanediol, 1,3-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,5-pentanediol, 2,3-pentanediol, 2,4-pentanediol, 2,5-pentanediol, 3,4-, pentanediol, and 3,5-pentanediol. A preferred alcohol is isopropanol. The second solvent may also be a mixture of alcohols selected from the aforementioned group.
Microparticles of the micronized hydrophobic agent may be prepared by a variety of methods including, for example, spray drying, interfacial polymerization, hot melt encapsulation, phase separation encapsulation, spontaneous emulsion, solvent evaporation microencapsulation, solvent removal microencapsulation, coacervation, and low temperature microsphere formation. One preferred method of preparing microparticles of the hydrophobic agent is by performing phase inversion nanoencapsulation (PIN).
According to another aspect of the invention, microparticles are provided. The microparticles may be produced by the processes described above. The microencapsulated product may be composed of particles having various sizes. In one embodiment, more than 90% of the particles have a size less than 1 micron.
According to still another aspect of the invention, a composition comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron is provided. The preparation is composed of less than 5% polymer carrier and is free of surfactant. In one embodiment, the preparation is free of polymer carrier.
The invention, also provides in some aspects a composition comprising a preparation of micronized hydrophobic agent having an average particle size of less than 1 micron, wherein the preparation is free of polymer carrier and wherein the crystallinity of the micronized hydrophobic agent is at least 50% of the crystallinity of the non-micronized hydrophobic agent. In one embodiment, the crystallinity is at least 75%. In another embodiment, the crystallinity is greater than 90%.
The invention also encompasses methods for delivering a hydrophobic agent to a subject, by administering an encapsulated product including the agent, to the subject. The solid preparation of the micronized hydrophobic agent having an average particle size of less than 1 micron, composed of less than 5% polymer and free of surfactant is administered orally. In one embodiment, the bioactivity of the hydrophobic agent is retained. In another embodiment, the micronized hydrophobic agent has at least a 5% increase in relative bioavailability compared to the non-micronized hydrophobic agent. In some embodiments, the preparation is free of polymer.
In other aspects, the invention provides methods for delivering an agent to a subject by administering microparticles of a micronized hydrophobic agent encapsulated by phase inversion nanoencapsulation. The average microparticle size is less than 1 micron and the preparation, is composed of less than 5% polymer and is free of surfactant. The microencapsulated micronized hydrophobic agent may be administered orally. In one embodiment, the bioactivity of the hydrophobic agent is retained. In another embodiment, the micronized hydrophobic agent has at least a 5% increase in relative bioavailability compared to the non-micronized hydrophobic agent. In some embodiments, the preparation is free of polymer.
The invention also provides a method for achieving 100% bioactivity. The method comprises orally administering to the subject a solid preparation of micronized hydrophobic agent having an average particle size of less than 1 micron wherein 100% of the orally administered agent is bioactive. In an embodiment, the preparation is composed of less than 5% polymer and is free of surfactant. In some embodiments, the preparation is free of polymer.
The foregoing aspects of the invention as well as various objects, features, and advantages are discussed in greater detail below.